scholarly journals MEK-Specific Inhibitor U0126 Blocks Spread of Borna Disease Virus in Cultured Cells

2001 ◽  
Vol 75 (10) ◽  
pp. 4871-4877 ◽  
Author(s):  
Oliver Planz ◽  
Stephan Pleschka ◽  
Stephan Ludwig
Keyword(s):  
Disease Virus ◽  
Cultured Cells ◽  
Antiviral Drug ◽  
Specific Inhibitor ◽  
Host Cells ◽  
Virus Spread ◽  
Focus Formation ◽  
Borna Disease Virus ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a highly neurotropic virus that causes Borna disease, a virus-induced immune-mediated encephalomyelitis, in a variety of warm-blooded animals. Recent studies reported that BDV can be detected in patients with psychiatric disorders. BDV is noncytopathic, replicates in the nucleus of infected cells, and spreads intraaxonally in vivo. Upon infection of susceptible cultured cells, virus can be detected in foci. Little is known about the cellular components required for BDV replication. Here, we show that the cellular Raf/MEK/ERK signaling cascade is activated upon infection with BDV. In the presence of the MEK-specific inhibitor U0126, cells get infected with BDV; however, there is a block in virus spread to neighboring cells. The effect of the inhibitor on virus spread was still observed when the compound was added 2 h postinfection but not if treatment was initiated as late as 4 h after infection. Our results provide new insights into the BDV-host cell interaction and show that virus infection can be controlled with drugs interfering with a cellular signaling pathway. Since concentrations of the MEK inhibitor required to block BDV focus formation are not toxic for the host cells, our finding may be important with respect to antiviral drug development.

scholarly journals Borna Disease Virus Phosphoprotein Binds a Neurite Outgrowth Factor, Amphoterin/HMG-1

2001 ◽  
Vol 75 (18) ◽  
pp. 8742-8751 ◽  
Author(s):  
Wataru Kamitani ◽  
Yuko Shoya ◽  
Takeshi Kobayashi ◽  
Makiko Watanabe ◽  
Byeong-Jae Lee ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Disease Virus ◽  
Cell Lines ◽  
Cultured Cells ◽  
Borna Disease Virus ◽  
P24 Protein ◽  
Infected Cells ◽  
The Brain ◽  
Borna Disease

ABSTRACT The Borna disease virus (BDV) p24 phosphoprotein is an abundant protein in BDV-infected cultured cells and animal brains. Therefore, there is a possibility that binding of the p24 protein to cellular factor(s) induces functional alterations of infected neural cells in the brain. To identify a cellular protein(s) that interacts with BDV p24 protein, we performed far-Western blotting with extracts from various cell lines. Using recombinant p24 protein as a probe, we detected a 30-kDa protein in all cell lines examined. Binding between the 30-kDa and BDV p24 proteins was also demonstrated using BDV p24 affinity and ion-exchange chromatography columns. Microsequence analysis of the purified 30-kDa protein revealed that its N terminus showed complete homology with rat amphoterin protein, which is a neurite outgrowth factor abundant in the brain during development. Mammalian two-hybrid and immunoprecipitation analyses also confirmed that amphoterin is a specific target for the p24 protein in vivo. Furthermore, we showed that infection by BDV, as well as purified p24 protein in the medium, significantly decreased cell process outgrowth of cells grown on laminin, indicating the functional inhibition of amphoterin by interaction with the p24 protein. Immunohistochemical analysis revealed decreased levels of amphoterin protein at the leading edges of BDV-infected cells. Moreover, the expression of the receptor for advanced glycation end products, of which the extracellular moiety is a receptor for amphoterin, was not significantly activated in BDV-infected cells during the process of extension, suggesting that the secretion of amphoterin from the cell surface is inhibited by the binding of the p24 protein. These results suggested that BDV infection may cause direct damage in the developing brain by inhibiting the function of amphoterin due to binding by the p24 phosphoprotein.

scholarly journals 1-β-d-Arabinofuranosylcytosine Inhibits Borna Disease Virus Replication and Spread

2002 ◽  
Vol 76 (12) ◽  
pp. 6268-6276 ◽  
Author(s):  
Jeffrey J. Bajramovic ◽  
Sylvie Syan ◽  
Michel Brahic ◽  
Juan Carlos de la Torre ◽  
Daniel Gonzalez-Dunia
Keyword(s):  
Disease Virus ◽  
Measles Virus ◽  
Rna Virus ◽  
Neurological Diseases ◽  
Borna Disease Virus ◽  
Negative Strand ◽  
Neuropsychiatric Diseases ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a nonsegmented, negative-strand RNA virus that causes neurological diseases in a variety of warm-blooded animal species. There is general consensus that BDV can also infect humans, being a possible zoonosis. Although the clinical consequences of human BDV infection are still controversial, experimental BDV infection is a well-described model for human neuropsychiatric diseases. To date, there is no effective treatment against BDV. In this paper, we demonstrate that the nucleoside analog 1-β-d-arabinofuranosylcytosine (Ara-C), a known inhibitor of DNA polymerases, inhibits BDV replication. Ara-C treatment inhibited BDV RNA and protein synthesis and prevented BDV cell-to-cell spread in vitro. Replication of other negative-strand RNA viruses such as influenza virus or measles virus was not inhibited by Ara-C, underscoring the particularity of the replication machinery of BDV. Strikingly, Ara-C treatment induced nuclear retention of viral ribonucleoparticles. These findings could not be attributed to known effects of Ara-C on the host cell, suggesting that Ara-C directly inhibits the BDV polymerase. Finally, we show that Ara-C inhibits BDV replication in vivo in the brain of infected rats, preventing persistent infection of the central nervous system as well as the development of clinical disease. These findings open the way to the development of effective antiviral therapy against BDV.

scholarly journals Borna Disease Virus Infection, a Human Mental-Health Risk

2003 ◽  
Vol 16 (3) ◽  
pp. 534-545 ◽  
Author(s):  
Liv Bode ◽  
Hans Ludwig
Keyword(s):  
Disease Virus ◽  
Enzyme Linked Immunosorbent Assay ◽  
Diagnostic Systems ◽  
Cross Sectional ◽  
Borna Disease Virus ◽  
Pros And Cons ◽  
The Impact ◽  
Borna Disease

SUMMARY This article focuses on human Borna disease virus (BDV) infections, most notably on the development of valid diagnostic systems, which have arisen as a major research issue in the past decade. The significance of a novel modular triple enzyme-linked immunosorbent assay that is capable of specifically measuring anti-BDV antibodies as well as major structural proteins N (p40) and P (p24) in the blood, either as free antigens in the plasma or as antibody-bound circulating immune complexes (CICs), is explained. The impact of CICs and plasma antigen, which indicate periods of antigenemia in the course of BDV infection, along with other infection markers that are still in use is discussed. The review further provides new insight into possible links of BDV to human diseases, summarizing cross-sectional and longitudinal data which correlate acute depression with the presence and amount of antigen and CICs. Moreover, BDV prevalence in healthy people is reevaluated, suggesting that this was previously underestimated. Antiviral efficacy of amantadine, in vivo and in vitro, is outlined as well, with emphasis on wild-type (human and equine) versus laboratory strains. Finally, the pros and cons of the association of BDV with human disease, as detailed in the literature, are critically discussed and related to our data and concepts. This article supports existing correlative evidence for a pathogenic role of BDV infection in particular human mental disorders, in analogy to what has been proven for a variety of animal species.

scholarly journals Mechanism of Borna Disease Virus Entry into Cells

1998 ◽  
Vol 72 (1) ◽  
pp. 783-788 ◽  
Author(s):  
Daniel Gonzalez-Dunia ◽  
Beatrice Cubitt ◽  
Juan Carlos de la Torre
Keyword(s):  
Disease Virus ◽  
Virus Entry ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Animal Cells ◽  
Borna Disease Virus ◽  
C Terminus ◽  
Surface Receptor ◽  
Infected Cells ◽  
Borna Disease

ABSTRACT We have investigated the entry pathway of Borna disease virus (BDV). Virus entry was assessed by detecting early viral replication and transcription. Lysosomotropic agents (ammonium chloride, chloroquine, and amantadine), as well as energy depletion, prevented BDV infection, indicating that BDV enters host cells by endocytosis and requires an acidic intracellular compartment to allow membrane fusion and initiate infection. Consistent with this hypothesis, we observed that BDV-infected cells form extensive syncytia upon low-pH treatment. Entry of enveloped viruses into animal cells usually requires the membrane-fusing activity of viral surface glycoproteins (GPs). BDV GP is expressed as two products of 84 and 43 kDa (GP-84 and GP-43, respectively). We show here that only GP-43 is present at the surface of BDV-infected cells and therefore is likely the viral polypeptide responsible for triggering fusion events. We also present evidence that GP-43, which corresponds to the C terminus of GP-84, is generated by cleavage of GP-84 by the cellular protease furin. Hence, we propose that BDV GP-84 is involved in attachment to the cell surface receptor whereas its furin-cleaved product, GP-43, is involved in pH-dependent fusion after internalization of the virion by endocytosis.

scholarly journals Alpha/Beta Interferon Promotes Transcription and Inhibits Replication of Borna Disease Virus in Persistently Infected Cells

2001 ◽  
Vol 75 (17) ◽  
pp. 8216-8223 ◽  
Author(s):  
Peter Staeheli ◽  
Maria Sentandreu ◽  
Axel Pagenstecher ◽  
Jürgen Hausmann
Keyword(s):  
Disease Virus ◽  
Cultured Cells ◽  
Genome Replication ◽  
Wild Type ◽  
Endogenous Virus ◽  
Viral Mrnas ◽  
Borna Disease Virus ◽  
Persistently Infected ◽  
Alpha Beta ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a noncytolytic RNA virus that can replicate in the central nervous system (CNS) of mice. This study shows that BDV multiplication was efficiently blocked in transgenic mice that express mouse alpha-1 interferon (IFN-α1) in astrocytes. To investigate whether endogenous virus-induced IFN might similarly restrict BDV, we usedIFNAR 0/0 mice, which lack a functional alpha/beta IFN (IFN-α/β) receptor. As would be expected if virus-induced IFN were important to control BDV infection, we found that cultured embryo cells of IFNAR 0/0 mice supported viral multiplication, whereas cells from wild-type mice did not. Unexpectedly, however, BDV spread through the CNSs ofIFNAR 0/0 and wild-type mice with similar kinetics, suggesting that activation of endogenous IFN-α/β genes in BDV-infected brains was too weak or occurred too late to be effective. Surprisingly, Northern blot analysis showed that the levels of the most abundant viral mRNAs in the brains of persistently infectedIFNAR 0/0 mice were about 20-fold lower than those in wild-type mice. In contrast, genomic viral RNA was produced in about a 10-fold excess in the brains ofIFNAR 0/0 mice. Human IFN-α2 similarly enhanced transcription and simultaneously repressed replication of the BDV genome in persistently infected Vero cells. Thus, in persistently infected neurons and cultured cells, IFN-α/β appears to freeze the BDV polymerase in the transcriptional mode, resulting in enhanced viral mRNA synthesis and suppressing viral genome replication.

scholarly journals Generation and Characterization of a Recombinant Vesicular Stomatitis Virus Expressing the Glycoprotein of Borna Disease Virus

2007 ◽  
Vol 81 (11) ◽  
pp. 5527-5536 ◽  
Author(s):  
Mar Perez ◽  
Roberto Clemente ◽  
Clinton S. Robison ◽  
E. Jeetendra ◽  
Himangi R. Jayakar ◽  
...  
Keyword(s):  
Disease Virus ◽  
Vesicular Stomatitis Virus ◽  
Cell Entry ◽  
Surface Glycoprotein ◽  
Free Virus ◽  
Borna Disease Virus ◽  
Virus Family ◽  
Vesicular Stomatitis ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is an enveloped virus with a nonsegmented negative-strand RNA genome whose organization is characteristic of mononegavirales. However, based on its unique genetics and biological features, BDV is considered to be the prototypic member of a new virus family, Bornaviridae, within the order Mononegavirales. BDV cell entry occurs via receptor-mediated endocytosis, a process initiated by the recognition of an as yet unidentified receptor at the cell surface by the BDV surface glycoprotein (G). The paucity of cell-free virus associated with BDV infection has hindered studies aimed at the elucidation of cellular receptors and detailed mechanisms involved in BDV cell entry. To overcome this problem, we generated and characterized a replication-competent recombinant vesicular stomatitis virus expressing BDV G (rVSVΔG*/BDVG). Cells infected with rVSVΔG*/BDVG produced high titers (107 PFU/ml) of cell-free virus progeny, but this virus exhibited a highly attenuated phenotype both in cell culture and in vivo. Attenuation of rVSVΔG*/BDVG was associated with a delayed kinetics of viral RNA replication and altered genome/N mRNA ratios compared to results for rVSVΔG*/VSVG. Likewise, incorporation of BDV G into virions appeared to be restricted despite its high levels of expression and efficient processing in rVSVΔG*/BDVG-infected cells. Notably, rVSVΔG*/BDVG recreated the cell tropism and entry pathway of bona fide BDV. Our results indicate that rVSVΔG*/BDVG represents a unique tool for the investigation of BDV G-mediated cell entry, as well as the roles of BDV G in host immune responses and pathogenesis associated with BDV infection.

Amantadine and human Borna disease virus in vitro and in vivo in an infected patient with bipolar depression

The Lancet ◽  
1997 ◽  
Vol 349 (9046) ◽  
pp. 178-179 ◽  
Author(s):  
Liv Bode ◽  
Detlef E Dietrich ◽  
Roman Stoyloff ◽  
Hinderk M Emrich ◽  
Hanns Ludwig
Keyword(s):  
Disease Virus ◽  
Infected Patient ◽  
Bipolar Depression ◽  
Borna Disease Virus ◽  
Borna Disease

Age- and host-dependent control of Borna disease virus spread in the developing brains of gerbils and rats

2003 ◽  
Vol 5 (13) ◽  
pp. 1195-1204 ◽  
Author(s):  
Byeong-Jae Lee ◽  
Makiko Watanabe ◽  
Wataru Kamitani ◽  
Satoko Baba ◽  
Makiko Yamashita ◽  
...  
Keyword(s):  
Disease Virus ◽  
Virus Spread ◽  
Borna Disease Virus ◽  
Borna Disease

scholarly journals Modeling Borna Disease Virus In Vitro Spread Reveals the Mode of Antiviral Effect Conferred by an Endogenous Bornavirus-Like Element

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
Kwang Su Kim ◽  
Yusuke Yamamoto ◽  
Shinji Nakaoka ◽  
Keizo Tomonaga ◽  
Shingo Iwami ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Disease Virus ◽  
Virus Replication ◽  
Ground Squirrel ◽  
Cultured Cells ◽  
Antiviral Effect ◽  
Endogenous Retroviruses ◽  
Virus Spread ◽  
Borna Disease

ABSTRACT Endogenous retroviruses have demonstrated exaptation during long-term evolution with hosts, e.g., resulting in acquisition of antiviral effect on related extant viral infections. While empirical studies have found that an endogenous bornavirus-like element derived from viral nucleoprotein (itEBLN) in the ground squirrel genome shows antiviral effect on virus replication and de novo infection, the antiviral mechanism, dynamics, and quantitative effect of itEBLN remain unknown. In this study, we experimentally and theoretically investigated the dynamics of how an extant bornavirus, Borna disease virus 1 (BoDV-1), spreads and replicates in uninfected, BoDV-1-infected, and itEBLN-expressing cultured cells. Quantifying antiviral effect based on time course data sets, we found that the antiviral effects of itEBLN are estimated to be 75% and 34% on intercellular virus spread and intracellular virus replication, respectively. This discrepancy between intercellular virus spread and intracellular viral replication suggests that viral processes other than the replication of viral ribonucleoprotein complex (RNP) contributed to the suppression of virus spread in itEBLN-expressing cells. Because itEBLN binds to the BoDV-1 RNP, the suppression of viral RNP trafficking can be an attractive candidate explaining this discrepancy. IMPORTANCE Accumulating evidence suggests that some endogenous viral elements (EVEs), including endogenous retroviruses and endogenous nonretroviral virus elements, have acquired functions in the host as a result of long-term coevolution. Recently, an endogenous bornavirus-like element (itEBLN) found in the ground squirrel genome has been shown to have antiviral activity against exogenous bornavirus infection. In this study, we first quantified bornavirus spread in cultured cells and then calculated the antiviral activity of itEBLN on bornavirus infection. The calculated antiviral activity of itEBLN suggests its suppression of multiple processes in the viral life cycle. To our knowledge, this is the first study quantifying the antiviral activity of EVEs and speculating on a model of how some EVEs have acquired antiviral activity during host-virus arms races.

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